Monograph on the Potential Human Reproductive and ... - OEHHA

276 CHAPIN ET AL.
tyrosine-hydroxlyase monoclonal antibody reactivity
[number of rats not indicated]. Most statistical analyses
were performed using ANOVA techniques. Activity data
were analyzed using repeated measures ANOVA to
examine activity in 2-hr intervals, as well as across the
dark, light, or full 24-hr period. Student t-tests were used
to compare catecholamine levels.
Spontaneous motor activity in rats treated with bisphenol
A increased in a dose-dependent manner over
the 0.087–87 nmol range, with significance on pair-wise
comparison with controls at dose levels Z0.87 nmol [198
ng]. Activity was increased in both the dark and light
periods. Tyrosine hydroxylase activity was reduced in
bisphenol A-treated rats, compared to controls. [Quantification
of immunohistochemical sections was not
provided.] Gene expression patterns in the midbrain
differed in bisphenol A and 6-hydroxydopamine-treated
animals.
The authors concluded that neonatal exposure to
bisphenol A was associated with an increase in spontaneous
motor activity and reduced tyrosine hydroxylase
activity. They hypothesized that bisphenol A may cause a
deficit in the development of mesostriatal dopaminergic
neurons, and that this increase either is greater than that
produced by 6-hydroxydopamine lesions or involves
additional neurochemical systems. A follow-up study
(Masuo et al., 2004b) addressed these issues. The authors
also proposed that bisphenol A-exposed rats can serve as
animal models of attention deficit-hyperactivity disorder.
Strengths/Weaknesses: A significant weakness is the
inability to correlate the internal exposure to bisphenol A
provided by the intracisternal route with that seen by the
oral route.
Utility (Adequacy) for CERHR Evaluation Process:
This study is inadequate for the evaluation process due
to uncertainties around the intracisternal route of
administration.
Masuo et al. (2004b), funded by the New Energy and
Industrial Technology Development Organization, the
Ministry of the Environment, and the Ministry of
Economy, Trade, and Industry, Japan, followed up their
previous study (Masuo et al., 2004a) with additional gene
expression microarrays to elucidate potential molecular
pathways associated with the effects of an acute,
neonatal exposure to 6-hydroxydopamine, bisphenol A,
nonylphenol, diethylhexyl phthalate, or dibutyl
phthalate on spontaneous motor activity levels at 4–5
weeks of age. Pregnant Wistar rats were housed in
acrylic cages with free access to tap water and laboratory
chow (Oriental Yeast) and maintained on a 12-hr light/
12-hr dark cycle. In the 6-hydroxydopamine group,
5-day-old male pups, each about 10 g, were first
pretreated with 25 mg/kg desipramine by i.p. injection
(to protect noradrenergic neurons from the effects of 6hydroxydopamine)
and then given 6-hydroxydopamine
intracisternally 30 min later. PND 5 male pups in other
groups were intracisternally injected with olive oil
vehicle, 87 nM bisphenol A [19.8 lg] [purity not
provided], nonylphenol, diethylhexyl phthalate, or
dibutyl phthalate. [Only the bisphenol A experiments
will be discussed here.] Following treatments,
pups were randomly fostered to lactating dams (5–7
pups/per dam) and weaned at 3 weeks of age. At 4–5
weeks of age, the spontaneous motor activity of bisphenol
A treated rats was compared to vehicle treated
rats (n 5 6 or 7/group) using an automated activitymonitoring
system over a 12-hr light/12-hr dark cycle.
Bisphenol A and vehicle-treated rats were killed at 8–10
weeks of age and the striatum and midbrain were
harvested. RNA was extracted from 2 pooled striata/rat
(n 5 3/group) or 1 midbrain/rat (n 5 3/group) for cDNA
microarray analyses. Gene expression values were
evaluated relative to those of control-treated rats.
Repeated measures ANOVA was used for statistical
analyses of spontaneous motor activity during 2-hr
time intervals. Statistics were not described for microarray
results.
Neonatal exposure to bisphenol A in male rats
increased spontaneous motor activity significantly at 4–
5 weeks during both the dark and light periods of the
cycle when compared to controls. Gene expression
profiles examined at 8–10 weeks of age for select genes
potentially impinging on dopamine function and/or
other pathways were altered in the adult striatum and
midbrain of bisphenol A treated mice. The authors
concluded that neonatal exposure to bisphenol A
resulted in elevated spontaneous motor activity during
both the light and dark phases. 6-Hydroxydopamine
lesions increased motor activity only during the dark
period. Comparisons of genetic expression in 6-hydroxydopamine
and bisphenol A-treated rats suggested that
the effects of bisphenol A may be mediated by alterations
in dopamine as well as other systems. This profile of
adverse effects was suggested to potentially serve as a
model for human hyperactivity disorders.
Strengths/Weaknesses: A significant weakness is the
inability to correlate the internal exposure to bisphenol A
provided by the intracisternal route with that seen by the
oral route.
Utility (Adequacy) for CERHR Evaluation Process:
This study is inadequate for the evaluation process due
to uncertainties around the intracisternal route of
administration.
Ishido et al. (2005), support not indicated, examined
the effects of neonatal bisphenol A exposure of rats on
motor activity and gene expression in brain. Wistar rat
dams were fed MF diet (Oriental Yeast). Pups were born
from 10 pregnant dams and 5–7 male pups were assigned
to each dam. At 5 days of age, male pups were injected
intracisternally with vehicle (50% ethanol in olive oil) or
87 nmol [19.8 lg] bisphenol A. [No information was
provided on number of pups treated, purity of bisphenol
A, or caging and bedding materials.] Pups were
also treated with 2 nonylphenol compounds and 3
phthalate compounds, but results for those compounds
will not be discussed. Pups were weaned at 3 weeks of
age. Spontaneous motor activity was measured in pups
at 4–5 weeks of age. Rats were killed at 8 weeks of age,
and RNA was isolated from midbrain for microarray
analyses of gene expression. [The number of rats
examined was not reported for any endpoint.] Data
for spontaneous motor activity were analyzed by
ANOVA or Student t-test. [There were no statistical
analyses for gene expression data.]
Rats exposed to bisphenol A were significantly more
active during the nocturnal phase than control rats (by
B1.4–1.6-fold). In midbrains of 8-week-old rats, expression
levels were altered for 46 G protein-coupled receptor
genes, which are involved in dopaminergic neurotransduction
and many peptidergic neurotransduction
Birth Defects Research (Part B) 83:157–395, 2008